Response and safety of whole-brain radiotherapy plus temozolomide for patients with brain metastases of non-small-cell lung cancer: A meta-analysis

INTRODUCTION

Brain metastases are the most common intracranial malignant tumors.^{1, 2} Most of their primary lesions come from the lung.³ The brain metastasis rate of patients with non-small-cell lung cancer (NSCLC) is as high as 44%.⁴ NSCLC is the main cause of cancer death worldwide, and more than 20% of patients have brain metastasis during treatment.⁵ Brain involvement is an independent adverse prognostic factor with a median natural survival time of 1–2 months. The median survival time is only 4–12 months even with effective treatment.⁶ Therefore, brain metastasis is the main cause of treatment failure in patients with lung cancer. After receiving whole-brain radiation therapy (WBRT) as the standard treatment mode, the overall survival of NSCLC patients with brain metastasis can be prolonged by 3–6 months.^{7, 8} However, patients with brain metastasis have heavy tumor load, and radiotherapy alone has limited survival benefit, therefore the effect of WBRT alone is unsatisfied, and the recurrence rate in 6 months is as high as 70%.⁹

Platinum combined with third-generation cytotoxic chemotherapy drugs can bring survival benefits to brain metastasis of NSCLC patients.¹⁰ However, the existence of the blood–brain barrier limits the therapeutic effect and the treatment toxicity risk is significant increased.

Temozolomide (TMZ) is an imidazole tetrazine alkylating agent with antitumor activity. In vivo, TMZ is rapidly transformed into the active product 3-methyl-[triazine-1-]imidazole-4-formamide (MTIC). The therapeutic benefit of TMZ depends on its ability to alkylate/methylate DNA, which most often occurs at the N-7 or O-6 positions of guanine residues.¹¹ Studies have indicated that TMZ combined with WBRT had a higher response rate and longer progression-free survival time compared with WBRT alone in the treatment of patients with brain metastasis of NSCLC.¹² In the present work, we compared the objective response rate (ORR) and treatment-associated toxicity between WBRT+TMZ and WBRT only through pooling open published data, which may provide more evidence for brain metastases of NSCLC.

MATERIAL AND METHODS

RESULTS

Studies searching results

Four hundred eighty-seven clinical studies relevant to WBRT plus TMZ for patients with brain metastases of NSCLC were initially identified after searching the electronic databases. Twenty-five clinical trials fulfilled the inclusion criteria and were included in the meta-analysis. The study searching and inclusion procedure is shown in Figure 1. The main characteristics of the 25 studies included are shown in Table 1.

TABLE 1. Main features of the included clinical trials (n = 25)

Trials	Year	Country	WBRT+TMZ				WBRT
			Sample size	Age (years)	Gender (M/F)	KPS	Sample size	Age (years)	Gender (M/F)	KPS
Antondou13	2003	Greece	52	NA	NA	NA	51	NA	NA	NA
Chua14	2010	China	47	59 (38–78)	30/17	NA	48	62 (43–79)	32/16	NA
Hassler15	2013	Austria	22	69 (36–85)	NA	80 (7–100)	13	64 (54–78)	NA	80 (70–100)
Xie16	2007	China	25	NA	NA	NA	25	NA	NA	NA
Zhou17	2011	China	20	61	14/6	NA	22	55	15/7	NA
Shi18	2014	China	43	55 (38072)	25/18	NA	41	56 (38–73)	24/17	NA
Yang19	2015	China	23	NA	NA	NA	22	NA	NA	NA
Gu20	2015	China	52	59.5 ± 5.7	28/24	68.3 ± 5.2	50	58.2 ± 5.2	23/27	67.0 ± 4.5
Sun21	2016	China	30	59.0 ± 6.9	17/13	0.97 ± 0.76 (ECOG)	30	58.5 ± 7.6	16/14	0.90 ± 0.66 (ECOG)
Zhi22	2016	China	44	37–75	NA	NA	44	35–37	NA	NA
Liu23	2016	China	21	NA	NA	>70	16	NA	NA	>70
Mu24	2016	China	29	NA	NA	NA	29	NA	NA	NA
Xu25	2016	China	40	NA	NA	NA	40	NA	NA	NA
Zhao26	2016	China	30	38–69	16/14	NA	30	36–68	17/13	NA
Wang27	2017	China	37	NA	18/19	≧70	41	NA	22/19	≧70
Teng28	2017	China	26	55.6 ± 7.8	16/10	ECOG(0–2)	25	56.8 ± 9.8	14/11	ECOG (0–2)
Sperduto29	2013	U.S	40	63	NA	NA	44	64	NA	NA
Li30	2015	China	18	54.5 (39–70)	10/8	NA	18	53.5 (37–72)	11/7	NA
Jiang31	2015	China	22	41–81	NA	NA	22	41–81	NA	NA
Deng12	2017	China	129	NA	60/69	ECOG (0–3)	109	42/67	NA	ECOG (0–3)
Wu32	2013	China	20	10/10	40–47	NA	20	10/10	40–47	NA
Hasyatti33	2018	China	25	NA	NA	NA	25	NA	NA	NA
Wan34	2018	China	28	54.6 ± 6.3	16/12	≧70	28	52.0 ± 6.3	15/13	≧70
Lu35	2019	China	40	53.57 ± 12.83	30/10	NA	40	23/17	54.27 ± 11.90	NA
Wang36	2020	China	25	NA	NA	NA	25	NA	NA	NA

• Abbreviations: ECOG, eastern cooperative oncology group; KPS, karnofsky performance scale; NA, not available.

Quality of the included studies

The methodical qualities of the 25 included studies were supposed to be moderate risk of bias. Most of the studies did not report the blinding status. The detailed quality assessment results are shown in Figure 2.

Objective response

Twenty-five studies reported the treatment response and the pooled results showed WBRT+TMZ can significantly improve the ORR compared WBRT alone (relative risk [RR] = 1.43, 95% confidence interval [CI] 1.32–1.55, p < 0.05) in a fixed effect model (Figure 3).

Treatment-related toxicity

Nine studies reported grade III–IV treatment-related hematological toxicity. The pooled results show that WBRT+TMZ significantly increased the grade III–IV hematological toxicity compared to WBRT alone (RR = 1.66, 95% CI 1.12–2.54, p < 0.05) under the fixed effect model. Nine trials compared the gastrointestinal toxicity between WBRT+TMZ and WBRT alone and the combined results indicate that grade III–IV gastrointestinal toxicity is significant increased in WBRT+TMZ compared to WBRT alone (RR = 1.72, 95% CI 1.29–2.30, p < 0.05) by the fixed effect model (Figure 4).

Publication bias

The Begg's funnel plots for ORR and toxicity were left–right asymmetrical, which indicates significant publication bias (Figure 5). Egger's line regression test also showed publication bias (p < 0.05).

DISCUSSION

After comprehensive systematic electronic searching, 25 clinical trials were included and quantitative analysis was performed. The pooled results indicated that the ORR in the WBRT+TMZ group was 1.43 times higher than that of the WBRT only group with statistical difference. However, WBRT+TMZ also significant increased the 66% grade III/IV hematological toxicity and the 72% grade III–IV gastrointestinal toxicity risk compared to WBRT alone. Therefore, the short-term ORR was improved by adding TMZ in the treatment of brain metastases from NSCLC, but the treatment-associated toxicity risk was also increased.

The present meta-analysis combined 25 open published clinical trials. Most of the work was done in China on the Chinese population. Only three studies were performed in United States, Greece, and Australia, therefore patient selection bias was ineluctable. In addition, the general methodical quality of the 25 studies was moderate. Most of the studies did not report the “blinding” status, which was at high risk of bias.

TMZ is a conventional chemotherapy drug applied in the treatment of intracranial tumors. As a new imidazole tetrazine alkylating agent, it has the characteristics of small molecular weight, wide antitumor spectrum, lipophilicity, and ability to pass through the blood–brain barrier.³⁷ The therapeutic benefit of TMZ depends on its ability to alkylate/methylate DNA, which most often occurs at the N-7 or O-6 positions of guanine residues. In some tumors, epigenetic silencing of the O-6-methylguanine-DNA methyltransferase gene prevents the synthesis of this enzyme, and as a consequence such tumors are more sensitive to killing by TMZ. After oral administration, TMZ concentration in brain tissue can reach 30–40% of that in blood, and the bioavailability is close to 100%.³⁸ Moreover, it can concentrate on tumor sites in vivo, with strong efficacy, certain selectivity, and fewer side effects. It has therefore has become the first-line chemotherapy drug for the clinical treatment of malignant brain tumors such as glioblastoma multiforme and anaplastic astrocytoma. Due to the satisfied anti-intracranial tumor effects of TMZ, several studies have investigated its effects on brain metastases diseases combined with WBRT. Chua¹⁴ and his colleges performed a randomized, open-label phase II clinical trial relevant to WBRT plus concomitant TMZ for the treatment of brain metastases from NSCLC. The authors recruited 95 brain metastases cases of NSCLC (47 in WBRT+TMZ, 49 in WBRT only) and found that the overall survival and central nervous system progression survival were not statistically different between WBRT+TMZ and WBRT only groups. The benefit of adding TMZ to WBRT was not confirmed. However, Deng¹² included a total of 238 NSCLC patients with brain metastases who received WBRT+TMZ or WBRT, respectively. The results showed adding TMZ to WBRT could improve the intracranial ORR and median progression-free survival compared with WBRT alone. However, side effects were also increased by adding TMZ, but the difference was not statistically significant and toxicities were well tolerated. Chua and Deng got inconclusive results on the ORR and survival for WBRT+TMZ versus WBRT alone for brain metastases of NSCLC.

Our meta-analysis combined 25 open published studies and indicated that the short-term ORR was improved by adding TMZ in the treatment of brain metastases from NSCLC, but the treatment-associated toxicity risk was also increased, which is in accordance with Deng's conclusion.

In conclusion, based on the present work, WBRT+TMZ can improve the ORR for brain metastases of NSCLC, but the risk of treatment-associated grade III/IV hematological toxicity and gastrointestinal toxicity was also increased compared to WBRT only. However, due to the aforementioned limitation of patient selection bias, the moderate methodical quality of included studies, and publication bias, more well-designed multicenter prospective randomized clinical controlled studies are urgently need to further validate the findings.